Project Summary/Abstract: Pancreatic Ductal Adenocarcinoma (PDA) is a highly aggressive and lethal disease in part due to the poor efficacy of current therapies. Therefore, my research focuses on the identification of better therapeutic strategies for PDAC. We recently developed an ex vivo, pancreatic ductal organoid system to culture normal pancreas, early-stage pancreatic cancer and PDAC-derived tissue inside a three dimensional, Matrigel matrix. Using these organoids, we identified gene expression alterations between normal and malignant cells using transcriptomic and proteomic approaches. The effect of these genes on tumor growth or maintenance will be functionally validated using orthotopically grafted organoid (OGO) mouse transplantation models. Validated key drivers will then be exploited to develop new therapeutic strategies. In addition to finding novel candidate drug targets, we have further investigated the role of Nrf2, a transcription factor we found to be important for PDAC progression, in the response of pancreatic tumors to traditional and novel therapeutic interventions. Our initial experiments suggest that Nrf2 serves as an anti-oxidant defense mechanism and that oxidants sensitize PDAC cells to translation inhibition, which can be used as a new therapeutic approach for the treatment of PDAC. We perform pre-clinical studies using genetically modified mouse models (GEMM) that express conditional oncogenic Kras and mutated p53 in the pancreas, as well as both mouse and human OGO models. The GEMM and OGO models develop PDAC, which accurately recapitulates human disease and provides excellent platforms to model therapeutic intervention. We will assess the efficacy of drug combinations identified from both gene expression changes as well as from drug screening approaches. Drug combinations to be tested include, but are not limited to, irreversible ErbB pathway inhibitors, inhibitors of AKT and MEK, several compounds with oxidant properties, and translation inhibitors. These efforts will focus on compounds that either already have FDA approval or have promising phase III trial results to facilitate rapid translation of our findings to the clinic. My role in these studies includes generation of an organoid library for global molecular analyses, as well as improving tools to identify candidate drug targets. Furthermore, I will continue to manage the in vivo preclinical studies that focus on discovering new therapeutic options for pancreatic cancer. Ultimately, my role will be to ensure the efficiency, reproducibility and accuracy of preclinical studies thereby facilitating the efficient translation of our findings into clinical trials.